The present invention relates to novel spiropiperidine derivatives which exhibit antagonistic action against tachykinin receptors (NK1, NK2 and NK3).
It is already known that NK1 receptors, NK2 receptors and NK3 receptors act as tachykinin receptors. A number of compounds are known to exhibit antagonistic action against one of these receptors. Recently, compounds which block as many subtypes as possible among these three subtypes have attracted a great deal of attention for use in methods of preventing or treating diseases induced by tachykinin. Compounds exhibiting antagonistic action against both NK1 and NK2 receptors are under investigation.
As a compound having antagonistic activities against both NK1 and NK2 receptors, for example, Compound A shown below is disclosed in EP-776893. However, it is not reported that this compound exhibits an antagonistic activity against NK3 receptor. 
The present invention relates to:
(1) a compound represented by the formula (I), or a pharmacologically acceptable salt, ester or other derivative thereof 
xe2x80x83{wherein,
R1 and R2 are the same or different and each represents an aryl group, a heteroaryl group, an aryl group substituted with 1 to 3 groups selected from Substituent Group A or a heteroaryl group substituted with 1 to 3 groups selected from Substituent Group A,
A represents a methylene group, a carbonyl group or a sulfonyl group,
B represents a single bond, a C1-4 alkylene group or a C2-4 alkenylene group,
D represents an oxygen atom or a sulfur atom,
E represents a C1-4 alkyene or a C2-4 alkenylene group, 
xe2x80x83[wherein,
G represents a C5-8 cycloalkene ring, a C5-9 cycloalkane ring substituted with 1 or 2 groups selected from Substituent Group B or a cycloalkene ring substituted with 1 or 2 groups selected from Substituent Group B,
Ar represents an aryl ring, a heteroaryl ring, an aryl ring substituted with 1 to 3 groups selected from Substituent Group A or a heteroaryl ring substituted with 1 to 3 groups selected from Substituent Group A],
R3 represents a lower alkyl group, and
n represents an integer from 1 to 3;
with the proviso that G does not include a group substituted with only an oxo group or a group substituted with only a lower alkanesulfonyl group},
[Substituent Group A]
halogen atoms, lower alkyl groups, halogeno-lower alkyl groups, lower alkoxy groups, lower alkoxycarbonyl groups, carboxyl groups, hydroxyl groups, lower aliphatic acyl groups, lower aliphatic acylamino groups, amino groups and cyano groups;
[Substituent Group B]
oxo groups, hydroxyl groups, carboxyl groups and thiol groups.
Among these, preferred compounds are:
(2) compounds wherein R1 represents an aryl group, a heteroaryl group or an aryl group substituted with 1 to 3 groups selected from Substituent Group A,
(3) compounds wherein R1 represents an aryl group or an aryl group substituted with 1 to 3 groups selected from Substituent Group A1 defined below,
(4) compounds wherein R2 represents an aryl group or an aryl group substituted with 1 to 3 groups selected from Substituent Group A,
(5) compounds wherein R2 represents an aryl group substituted with at least one group selected from Substituent Group A,
(6) compounds wherein A represents a carbonyl group,
(7) compounds wherein B represents a single bond,
(8) compounds wherein D represents an oxygen atom,
(9) compounds wherein E represents a C1-4 alkylene group,
(10) compounds wherein E represents a C2-3 alkylene group,
(11) compounds wherein 
(12) compounds wherein G represents a cyclopentane or cyclopentene ring which is substituted with one or two groups selected from Substituent Group B,
(13) compounds wherein G represents a cyclopentane or cyclopentene ring which is substituted with a hydroxy group,
(14) compounds wherein n represents 1 or 2, and
(15) compounds wherein n represents 2;
and pharmacologically acceptable salts, esters or other derivatives thereof.
[Substituent Group A1]
lower alkyl groups, halogeno-lower alkyl groups and lower alkoxy groups.
Of the above-described compounds, compounds which comprise a combination of factors selected from eight groups consisting of (2) and (3); (4) and (5); (6); (7); (8); (9) and (10); (11) to (13); and (14) and (15) are also preferred.
(16) The more preferred compounds are:
1-{2-[(2R)-(3,4-dichlorophenyl)-4-(3,4,5-trimethoxybenzoyl)morpholin-2-yl]ethyl}spiro[(2-hydroxy)indane-1,4xe2x80x2-piperidine],
1-{2-[(2R)-(3,4-dichlorophenyl)-4-(3,4,5-trimethoxybenzoyl)morpholin-2-yl]ethyl}spiro[(3-hydroxy)indane-1,4xe2x80x2-piperidine],
1-{2-[(2R)-(3,4-dichlorophenyl)-4-(3,4,5-trimethoxybenzoyl)morpholin-2-yl]ethyl}spiro[1H-indene-1,4xe2x80x2-piperidine],
1-{2-[(2R)-(3,4-dichlorophenyl)-4-(3,5-dimethoxybenzoyl)morpholin-2-yl]ethyl}spiro[(2-hydroxy)indane-1,4xe2x80x2-piperidine],
1-{2-[(2R)-(3,4-dichlorophenyl)-4-(3,5-dimethoxybenzoyl)morpholin-2-yl]ethyl}spiro[(3-hydroxy)indane-1,4xe2x80x2-piperidine], and
1-{2-[(2R)-(3,4-dichlorophenyl)-4-(3,5-dimethoxybenzoyl)morpholin-2-yl]ethyl}spiro[(1H-indene-1,4xe2x80x2-piperidine],
and pharmacologically acceptable salts, esters and other derivatives thereof.
(17) The most preferred compounds are:
1-{2-[(2R)-(3,4-dichlorophenyl)-4-(3,4,5-trimethoxybenzoyl)morpholin-2-yl]ethyl}spiro[(2-hydroxy)indane-1,4xe2x80x2-piperidine] and
1-{2-[(2R)-(3,4-dichlorophenyl)-4-(3,4,5-trimethoxybenzoyl)morpholin-2-yl]ethyl}spiro[(3-hydroxy)indane-1,4xe2x80x2-piperidine],
and pharmacologically acceptable salts, esters and other derivatives thereof.
A novel medicine of the present invention comprises as an effective ingredient a compound selected from any one of the compounds described above in (1) to (17), or a pharmacologically acceptable salt, ester or other derivative thereof, and it can be used particularly as a preventive agent or remedy for asthma and/or bronchitis, rhinitis, allergy and urinary incontinence.
In the formula (I), examples of the xe2x80x9caryl groupxe2x80x9d in the definitions of R1 and R2, the xe2x80x9caryl groupxe2x80x9d of the xe2x80x9caryl group substituted with 1 to 3 groups selected from Substituent Group Axe2x80x9d in the definitions of R1 and R2, and the xe2x80x9caryl groupxe2x80x9d of the xe2x80x9caryl group which may be substituted with a group selected from Substituent Group Axe2x80x9d in the definition of xe2x80x9cSubstituent Group Bxe2x80x9d, include C5-14 aromatic hydrocarbon groups such as phenyl, indenyl, naphthyl, phenanthrenyl and anthracenyl groups, of which phenyl groups are preferred.
Incidentally, the above-described xe2x80x9caryl groupxe2x80x9d may form a fused ring with a C3-10 cycloalkyl group and examples of such a group include 5-indanyl groups.
The xe2x80x9cheteroaryl groupxe2x80x9d in the definitions of R1 and R2, and the xe2x80x9cheteroaryl groupxe2x80x9d of the xe2x80x9cheteroaryl group substituted with 1 to 3 groups selected from Substituent Group Axe2x80x9d in the definitions of R1 and R2, mean a 5- to 7-membered aromatic heterocyclic group containing 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms. Examples include furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl and pyrazinyl groups. Among these, 5- to 7-membered aromatic heterocyclic groups each of which contain at least one nitrogen atom and may further contain an oxygen atom or sulfur atom are preferred. Examples include pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl and pyrazinyl groups, of which pyridyl, imidazolyl, oxazolyl, pyrazinyl and thiazolyl groups are more preferred.
Incidentally, the above-described xe2x80x9cheteroaryl groupxe2x80x9d may form a fused ring with another cyclic group. Examples of such a group include indolyl, benzofuryl, benzothienyl, benzoxazolyl, benzoimidazolyl, isoquinolyl, quinolyl and quinoxalyl groups.
Examples of the xe2x80x9clower alkyl groupxe2x80x9d in the definition of R3, [Substituent Group A] and [Substituent Group A1] and the xe2x80x9clower alkyl groupxe2x80x9d of the xe2x80x9clower alkyl group which may be substituted with a group selected from Substituent Group Axe2x80x9d in the definition of [Substituent Group B], include C1-6 straight or branched chain alkyl groups such as the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl and 2-ethylbutyl groups, of which C1-4 straight or branched chain alkyl groups are preferred.
Examples of the xe2x80x9cC1-4 alkylene groupxe2x80x9d in the definitions of B and E include C1-4 straight or branched chain alkylene groups such as methylene, methylmethylene, ethylene, propylene, trimethylene, tetramethylene, 1-methyltrimethylene, 2-methyltrimethylene and 3-methyltrimethylene groups.
With reference to B, C1-3 straight or branched chain alkylene groups are preferred.
With reference to E, C1-3 straight or branched chain alkylene groups are preferred, of which the ethylene and trimethylene groups are more preferred, and ethylene groups are most preferred.
Examples of the xe2x80x9cC2-4 alkenylene groupxe2x80x9d in the definitions of B and E include C2-4 straight or branched chain alkenylene groups such as ethenylene, 2-propenylene, 1-methyl-2-propenylene, 2-methyl-2-propenylene, 2-ethyl-2-propenylene and 2-butenylene groups, of which ethenylene, 2-propenylene and 3-butenylene groups are preferred, and ethenylene and 2-propenylene groups are more preferred.
Examples of the xe2x80x9cC5-8 cycloalkene ringxe2x80x9d, and the xe2x80x9cC5-8 cycloalkene ringxe2x80x9d of the xe2x80x9cC5-8 cycloalkene ring substituted with 1 or 2 groups selected from Substituent Group Bxe2x80x9d in the definition of G, include cyclopentene, cyclohexene, cycloheptene and cyclooctene rings, of which the xe2x80x9cC5-6 cycloalkene ringxe2x80x9d is preferred, and cyclopentene rings are more preferred.
Examples of the xe2x80x9cC5-8 cycloalkane ringxe2x80x9d of the xe2x80x9cC5-8 cycloalkane ring substituted with 1 or 2 groups selected from Substituent Group Bxe2x80x9d represented by G include cyclopentane, cyclohexane, cycloheptane and cyclooctane rings, of which the xe2x80x9cC5-6 cycloalkane ringxe2x80x9d is preferred, and cyclopentane rings are more preferred.
Examples of the xe2x80x9caryl ringxe2x80x9d, and the xe2x80x9caryl ringxe2x80x9d of the xe2x80x9caryl ring substituted with 1 to 3 groups selected from Substituent Group Axe2x80x9d in the definition of Ar, include C6-14 aromatic hydrocarbon rings such as benzene, indene, naphthalene, phenanthrene and anthracenyl rings, of which benzene rings are preferred.
The xe2x80x9cheteroaryl ringxe2x80x9d, and the xe2x80x9cheteroaryl ringxe2x80x9d of the xe2x80x9cheteroaryl ring substituted with 1 to 3 groups selected from Substituent Group Axe2x80x9d, each in the definition of Ar, means a 5- to 7-memered aromatic heterocyclic ring containing 1 to 3 sulfur atoms, oxygen atoms or/and nitrogen atoms. Examples include such as furan, thiophene, pyrrole, azepine, pyrazole, imidazole, oxazole, isoxazole, thiazole, isothiazole, 1,2,3-oxadiazole, triazole, tetrazole, thiadiazole, pyran, pyridine, pyridazine, pyrimidine and pyrazine rings. Among these, 5- to 7-membered aromatic heterocyclic rings which contains at least one nitrogen atom and which may also contain an oxygen atom or a sulfur atom are preferred and examples include such as pyrrole, azepine, pyrazole, imidazole, oxazole, isoxazole, thiazole, isothiazole, 1,2,3-oxadiazole, triazole, tetrazole, thiadiazole, pyridine, pyridazine, pyrimidine and pyrazine rings, of which pyridine, imidazole, oxazole, pyrazine and thiazole rings are more preferred.
Accordingly, examples of the group represented by the following formula: 
include 2-hydroxyindan-1,1-diyl (particularly, 2S-hydroxyindan-1,1-diyl), 3-hydroxyindan-1,1-diyl, 2,3-dihydroxyindan-1,1-diyl and inden-1,1-diyl.
The xe2x80x9chalogen atomsxe2x80x9d in the definition of [Substituent Group A] include fluorine, chlorine, bromine and iodine atoms, of which the fluorine and chlorine atoms are preferred.
The xe2x80x9chalogeno-lower alkyl groupsxe2x80x9d in the definition of [Substituent Group A] and [Substituent Group A1] mean the groups wherein a xe2x80x9chalogen atomxe2x80x9d, described above is attached to a xe2x80x9clower alkyl groupxe2x80x9d. Examples include trifluoromethyl, trichloromethyl, difluoromethyl, dichloromethyl, dibromomethyl, fluoromethyl, 2,2,2-trichloroethyl, 2,2,2-trifluoroethyl, 2-bromoethyl, 2-chloroethyl, 2-fluoroethyl and 2,2-dibromoethyl groups, of which trifluoromethyl, 2-bromoethyl, 2-chloroethyl and 2-fluoroethyl groups are preferred.
The xe2x80x9clower alkoxy groupsxe2x80x9d in the definitions of [Substituent Group A] and [Substituent Group A1], and the xe2x80x9clower alkoxy groupsxe2x80x9d of the xe2x80x9clower alkoxycarbonyl groupxe2x80x9d in the definition of [Substituent Group A] mean the group wherein a xe2x80x9clower alkyl groupxe2x80x9d, described above, is attached to an oxygen atom. Examples include C1-6 straight or branched chain alkoxy groups such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, s-butoxy, tert-butoxy, n-pentoxy, isopentoxy, 2-methylbutoxy, neopentoxy, n-hexyloxy, 4-methylpentoxy, 3-methylpentoxy, 2-methylpentoxy, 3,3-dimethylbutoxy, 2,2-dimethylbutoxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 1,3-dimethylbutoxy and 2,3-dimethylbutoxy groups, of which C1-4 straight or branched chain alkoxy groups are preferred.
The xe2x80x9clower aliphatic acyl groupsxe2x80x9d and the xe2x80x9clower aliphatic acyl groupsxe2x80x9d of the xe2x80x9clower aliphatic acylamino groupsxe2x80x9d in the definition of [Substituent Group A] means C2-7 aliphatic acyl groups. Examples include formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, pivaloyl, valeryl and isovaleryl groups, of which acetyl and propionyl groups are preferred.
R1 is, preferably, an aryl group, a heteroaryl group or an aryl group substituted with 1 to 3 groups selected from Substituent Group A; more preferably, is an aryl group or an aryl group substituted with 1 to 3 groups selected from Substituent Group A1; still more preferably, is an aryl group substituted with 1 to 3 groups selected from Substituent Group A1; and, most preferably, is an aryl group substituted with 1 to 3 lower alkoxy groups.
R2 is, preferably, an aryl group substituted with 1 to 3 groups selected from Substituent Group A; more preferably, is an aryl group substituted with 1 to 3 groups selected from Substituent Group A; still more preferably, is an aryl group substituted with 1 to 3 halogen atoms; and, most preferably, is a phenyl group substituted with 1 to 3 halogen atoms.
The following formula preferably represents a group wherein the carbon atom next to the carbon atom which constitutes the spiro bond between the group G and the piperidine ring, and the carbon atom next to the former carbon atom constitute a part of the cyclic group Ar and also a part of the cyclic group G. 
The compounds (I) of the present invention can form and can be used in the form of a xe2x80x9cpharmacologically acceptable saltxe2x80x9d (referred to herein as xe2x80x9csaltxe2x80x9d).
Preferred examples of the salt comprising the compounds (I) of the invention and an acid include inorganic acid salts such as hydrohalic acid salts (e.g. hydrofluoride, hydrochloride, hydrobromide, hydroiodide, etc.), nitrate, perchlorate, sulfate, phosphate and the like; organic acid salts such as lower alkanesulfonate (e.g. methanesulfonate, trifluoromethanesulfonate, ethanesulfonate, etc.), arylsulfonate (e.g. benzenesulfonate, p-toluenesulfonate, etc.), acetic acid, malic acid, fumarate, succinate, citrate, tartrate, oxalate, maleate and the like; and amino acid salts such as glycine salts, lysine salts, arginine salts, ornithine salts, glutamate, asparate and the like; of which the hydrohalic acid salts and organic acid salts are more preferred, the hydrohalic acid salts are still more preferred and the hydrochloride is most preferred.
Preferred examples of the salt composed of the invention compound (I) and a base, on the other hand, include metal salts, for example, salts of an alkali metal such as sodium salts, potassium salts and lithium salts, salts of an alkaline earth metal such as calcium salts and magnesium salts, aluminum salts and iron salts; amine salts, for example, inorganic salts such as ammonium salts and organic salts such as t-octylamine salts, dibenzylamine salts, morpholine salts, glucosamine salts, phenylglycine alkyl ester salts, ethylenediamine salts, N-methylglucamine salts, guanidine salts, diethylamine salts, triethylamine salts, dicyclohexylamine salts, N,Nxe2x80x2-dibenzylethylenediamine salts, chloroprocaine salts, procaine salts, diethanolamine salts, N-benzylphenethylamine salts, piperazine salts, tetramethylammonium salts and tris(hydroxymethyl)aminomethane salts; aminoacid salts such as glycine salts, lysine salts, arginine salts, omithine salts, glutamic acid salts and aspartic acid salts.
Since the compounds (I) of the invention can be converted into the corresponding quaternary amine by modifying the nitrogen atom of the piperidino group in the molecule with the group R3, salts between such a cation-containing compound and an anion (there is no particular limitation on the anion provided that it serves as an anion, but examples include halogen ions such as a chloride ion and an iodide ion) are also embraced in the present invention.
Additionally, the compounds (I) of the present invention absorb water and have adsorbed water added thereto or become a hydrate, when they are allowed to stand in the air. Such hydrates are also embraced in the present invention.
The xe2x80x9cester or other derivative thereofxe2x80x9d means a compound wherein a functional group (e.g. a hydroxy group, carboxy group or amino group) is modified with a protecting group or the like and which can be converted into a compound (I) of the present invention after it has been administer ed to a living body. It can be determined whether a compound is such a derivative by administering it to an experimental animal, such as a rat or mouse, by intravenous injection, examining the body fluid of the animal after administration and detecting the original compound or a pharmaceutically acceptable salt thereof.
Since the compound (I) of the present invention can be converted into the corresponding ester, the xe2x80x9cesterxe2x80x9d thereof means such a pharmaceutically acceptable ester. Examples of the ester include xe2x80x9cesters of a hydroxyl groupxe2x80x9d and xe2x80x9cesters of a carboxy groupxe2x80x9d, an ester whose ester residue is a xe2x80x9cconventional protecting groupxe2x80x9d or a xe2x80x9cprotecting group which can be cleaved in vivo by a biological method such as hydrolysisxe2x80x9d.
The xe2x80x9cconventional protecting groupxe2x80x9d means a protecting group which can be cleaved by a chemical method such as hydrogenolysis, hydrolysis, electrolysis or photolysis.
Preferred examples of the xe2x80x9cconventional protecting groupxe2x80x9d for the xe2x80x9cester of a hydroxyl groupxe2x80x9d include the above-described xe2x80x9clower aliphatic acyl groupsxe2x80x9d; the above-described xe2x80x9caromatic acyl groupsxe2x80x9d; xe2x80x9ctetrahydropyranyl or tetrahydrothiopyranyl groupsxe2x80x9d such as tetrahydropyran-2-yl, 3-bromotetrahydropyran-2-yl, 4-methoxytetrahydropyran-4-yl, tetrahydrothiopyran-2-yl and 4-methoxytetrahydrothiopyran-4-yl groups; xe2x80x9ctetrahydrofuranyl or tetrahydrothiofuranyl groupsxe2x80x9d such as tetrahydrofuran-2-yl and tetrahydrothiofuran-2-yl groups; xe2x80x9csilyl groupsxe2x80x9d, for example, tri(lower alkyl)silyl groups such as trimethylsilyl, triethylsilyl, isopropyldimethylsilyl, t-butyldimethylsilyl, methyldiisopropylsilyl, methyl-di-t-butylsilyl and triisopropylsilyl groups and tri(lower alkyl)silyl groups substituted with 1 or 2 aryl groups such as diphenylmethylsilyl, diphenylbutylsilyl, diphenylisopropylsilyl and phenyldiisopropylsilyl groups; xe2x80x9calkoxymethyl groupsxe2x80x9d, for example, lower alkoxymethyl groups such as methoxymethyl, 1,1-dimethyl-1-methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl and tert-butoxymethyl groups, lower alkoxymethyl groups substituted with lower alkoxy groups such as 2-methoxyethoxymethyl groups and (halogeno lower alkoxy)methyl groups such as 2,2,2-trichloroethoxymethyl and bis(2-chloroethoxy)methyl groups; xe2x80x9csubstituted ethyl groupsxe2x80x9d, for example, ethyl groups substituted with a lower alkoxy group such as 1-ethoxyethyl and 1-(isopropoxy)ethyl groups and halogenated ethyl groups such as 2,2,2-trichloroethyl groups; xe2x80x9caralkyl groupsxe2x80x9d, for example, lower alkyl groups substituted with 1 to 3 aryl groups such as benzyl, xcex1-naphthylmethyl, xcex2-naphthylmethyl, diphenylmethyl, triphenylmethyl, xcex1-naphthyldiphenylmethyl and 9-anthrylmethyl groups and lower alkyl groups each substituted with 1 to 3 aryl groups having an aryl substituted with a lower alkyl, halogeno(lower alkyl), lower alkoxy, nitro, halogen or cyano group such as 4-methylbenzyl 2,4,6-trimethylbenzyl, 3,4,5-trimethylbenzyl, 3,5-di(trifluoromethyl)benzyl, 4-methoxybenzyl, 4-methoxyphenyldiphenylmethyl, 2-nitrobenzyl, 4-nitrobenzyl, 4-chlorobenzyl, 4-bromobenzyl and 4-cyanobenzyl groups; and the above-described xe2x80x9clower alkoxycarbonyl groupsxe2x80x9d.
Preferred examples of the xe2x80x9cconventional protecting groupxe2x80x9d for the xe2x80x9cester of a carboxyl groupxe2x80x9d include the above-described xe2x80x9clower alkyl groupsxe2x80x9d; lower alkenyl groups such as ethenyl, 1-propenyl, 2-propenyl, 1-methyl-2-propenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 2-methyl-2-propenyl, 2-ethyl-2-propenyl, 1-butenyl, 2-butenyl, 1-methyl-2-butenyl, 1-methyl-1-butenyl, 3-methyl-2-butenyl, 1-ethyl-2-butenyl, 3-butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl, 1-ethyl-3-butenyl, 1-pentenyl, 2-pentenyl, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl, 3-pentenyl, 1-methyl-3-pentenyl, 2-methyl-3-pentenyl, 4-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl and 5-hexenyl; lower alkynyl groups such as ethynyl, 2-propynyl, 1-methyl-2-propynyl, 2-butynyl, 1-methyl-2-butynyl, 1-ethyl-2-butynyl, 3-butynyl, 1-methyl-3-butynyl, 2-methyl-3-butynyl, 1-ethyl-3-butynyl, 2-pentynyl, 1-methyl-2-pentynyl, 3-pentynyl, 1-methyl-3-pentynyl, 2-methyl-3-pentynyl, 4-pentynyl, 1-methyl-4-pentynyl, 2-methyl-4-pentynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl and 5-hexynyl groups; the above-described xe2x80x9chalogeno-lower alkyl groupsxe2x80x9d; hydroxyxe2x80x9clower alkyl groupsxe2x80x9d such as 2-hydroxyethyl, 2,3-dihydroxypropyl, 3-hydroxypropyl, 3,4-dihydroxybutyl and 4-hydroxybutyl groups; xe2x80x9clower aliphatic acylxe2x80x9d-xe2x80x9clower alkyl groupsxe2x80x9d such as acetylmethyl groups; the above-described xe2x80x9caralkyl groupsxe2x80x9d; and the above-described xe2x80x9csilyl groupsxe2x80x9d.
The xe2x80x9cprotecting group which can be cleaved in vivo by a biological method such as hydrolysisxe2x80x9d means a protecting group which is cleaved in vivo by a biological method such as hydrolysis and forms a free acid or salt thereof. It can be determined whether a compound is such an ester by administering it to an experimental animal, such as a rat or mouse, by intravenous injection, examining the body fluid of the animal after administration and detecting the original compound or a pharmaceutically acceptable salt thereof.
Preferred examples of the xe2x80x9cprotecting group which can be cleaved in vivo by a biological method such as hydrolysisxe2x80x9d for the xe2x80x9cester of a hydroxyl groupxe2x80x9d include 1-(acyloxy)xe2x80x9clower alkyl groupsxe2x80x9d, for example, 1-(xe2x80x9clower aliphatic acylxe2x80x9doxy)xe2x80x9clower alkyl groupsxe2x80x9d such as formyloxymethyl, acetoxymethyl, dimethylaminoacetoxymethyl, propionyloxymethyl, butyryloxymethyl, pivaloyloxymethyl, valeryloxymethyl, isovaleryloxymethyl, hexanoyloxymethyl, 1-formyloxyethyl, 1-acetoxyethyl, 1-propionyloxyethyl, 1-butyryloxyethyl, 1-pivaloyloxyethyl, 1-valeryloxyethyl, 1-isovaleryloxyethyl, 1-hexanoyloxyethyl, 1-formyloxypropyl, 1-acetoxypropyl, 1-propionyloxypropyl, 1-butyryloxypropyl, 1-pivaloyloxypropyl, 1-valeryloxypropyl, 1-isovaleryloxypropyl, 1-hexanoyloxvpropyl, 1-acetoxybutyl, 1-propionyloxybutyl, 1-butyryloxybutyl, 1-pivaloyloxvbutyl, 1-acetoxypentyl, 1-propionyloxypentyl, 1-butyryloxypentyl, 1-pivaloyloxypentyl and 1-pivaloyl-oxyhexyl groups, 1-(xe2x80x9ccycloalkylxe2x80x9dcarbonyloxy)xe2x80x9clower alkyl groupsxe2x80x9d such as cyclopentylcarbonyloxymethyl, cyclohexylcarbonyloxymethyl, 1-cyclopentylcarbonyloxyethyl, 1-cyclohexylcarbonyloxyethyl, 1-cyclopentylcarbonyloxypropyl, 1-cyclohexyl-carbonyloxypropyl, 1-cyclopentylcarbonyloxybutyl and 1-cyclohexyl-carbonyloxybutyl groups, and 1-(xe2x80x9caromatic acylxe2x80x9doxy)xe2x80x9clower alkyl groupsxe2x80x9d such as benzoyloxymethyl groups; (lower alkoxycarbonyloxy)alkyl groups such as methoxycarbonyloxymethyl, ethoxycarbonyloxymethyl, propoxycarbonyloxymethyl, isopropoxycarbonyloxymethyl, butoxycarbonyloxymethyl, isobutoxycarbonyloxymethyl, pentyloxycarbonyloxymethyl, hexyloxycarbonyloxymethyl, cyclohexyloxycarbonyloxymethyl, cyclohexyloxycarbonyloxy(cyclohexyl)methyl, 1-(methoxycarbonyloxy)ethyl, 1-(ethoxycarbonyloxy)ethyl, 1-(propoxycarbonyloxy)ethyl, 1-(isopropoxycarbonyloxy)ethyl, 1-(butoxycarbonyloxy)ethyl, 1-(isobutoxycarbonyloxy)ethyl, 1-(tert-butoxycarbonyloxy)ethyl, 1-(pentyloxycarbonyloxy)ethyl, 1-(hexyloxycarbonyloxy)ethyl, 1-(cyclopentyloxycarbonyloxy)ethyl, 1-(cyclopentyloxycarbonyloxy)propyl, 1-(cyclohexyloxycarbonyloxy)propyl, 1-(cyclopentyloxycarbonyloxy)butyl, 1-(cyclohexyloxycarbonyloxy)butyl, 1-(cyclohexyloxycarbonyloxy)ethyl, 1-(ethoxycarbonyloxy)propyl, 2-(methoxycarbonyloxy)ethyl, 2-(ethoxycarbonyloxy)ethyl, 2-(propoxycarbonyloxy)ethyl, 2-(isopropoxycarbonyloxy)ethyl, 2-(butoxycarbonyloxy)ethyl, 2-(isobutoxycarbonyloxy)ethyl, 2-(pentyloxycarbonyloxy)ethyl, 2-(hexyloxycarbonyloxy)ethyl, 1-methoxycarbonyloxy)propyl, 1-(ethoxycarbonyloxy)propyl, 1-(propoxycarbonyloxy)propyl, 1-(isopropoxycarbonyloxy)propyl, 1-(butoxycarbonyloxy)propyl, 1-(isobutoxycarbonyloxy)propyl, 1-(pentyloxycarbonyloxy)propyl, 1-(hexyloxycarbonyloxy)propyl, 1-(methoxycarbonyloxy)butyl, 1-(ethoxycarbonyloxy)butyl, 1-(propoxycarbonyloxy)butyl, 1-(isopropoxycarbonyloxy)butyl, 1-(butoxycarbonyloxy)butyl, 1-(isobutoxycarbonytoxy)butyl, 1-(methoxycarbonyloxy)pentyl, 1-(ethoxycarbonyloxy)pentyl, 1-(methoxycarbonyloxy)hexyl and 1-(ethoxycarbonyloxy)hexyl groups; and oxodioxolenyl-methyl groups such as (5-phenyl-2-oxo-1,3-dioxolen-4-yl)methyl, [5-(4-methylphenyl)-2-oxo-1,3-dioxolen-4-yl]methyl, [5-(4-methoxyphenyl)-2-oxo-1,3-dioxolen-4-yl]methyl, [5-(4-fluorophenyl)-2-oxo-1,3-dioxolen-4-yl]methyl, [5-(4-chlorophenyl)-2-oxo-1,3-dioxolen-4-yl]methyl, (2-oxo-1,3-dioxolen-4-yl)methyl, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl, (5-ethyl-2-oxo-1,3-dioxolen-4-yl)methyl, (5-propyl-2-oxo-1,3-dioxolen-4-yl)methyl, (5-isopropyl-2-oxo-1,3-dioxolen-4-yl)methyl and (5-butyl-2-oxo-1,3-dioxolen-4-yl)methyl groups: xe2x80x9cphthalidyl groupsxe2x80x9d such as phthalidyl, dimethylphthalidyl and dimethoxyphthalidyl groups: the above-described xe2x80x9clower aliphatic acyl groupsxe2x80x9d: the above-described xe2x80x9caromatic acyl groupsxe2x80x9d: xe2x80x9chalf ester salt residue of succinic acidxe2x80x9d: xe2x80x9cphosphate salt residuesxe2x80x9d: xe2x80x9cester forming residues such as with amino acidsxe2x80x9d: carbamoyl groups: carbamoyl groups substituted with 1 or 2 lower alkyl groups: and xe2x80x9c1-(acyloxy)alkyloxycarbonyl groupsxe2x80x9d such as pivaloyloxymethyloxycarbonyl, of which the xe2x80x9ccarbonyloxyalkyl groupsxe2x80x9d are preferred.
Preferred examples of the xe2x80x9cprotecting group which can be cleaved in vivo by a biological method such as hydrolysisxe2x80x9d for the xe2x80x9cester of a carboxy groupxe2x80x9d include xe2x80x9calkoxy lower alkyl groupsxe2x80x9d, for example, (lower alkoxy)(lower alkyl) groups such as methoxyethyl, 1-ethoxyethyl, 1-methyl-1-methoxyethyl, 1-(isopropoxy)ethyl, 2-methoxyethyl, 2-ethoxyethyl, 1,1-dimethyl-1-methoxyethyl, ethoxymethyl, n-propoxymethyl, isopropoxymethyl, n-butoxymethyl and tert-butoxymethyl groups, (lower alkoxy)lower alkyl groups substituted with lower alkoxy such as 2-methoxyethoxymethyl, xe2x80x9carylxe2x80x9doxyxe2x80x9clower alkyl groupsxe2x80x9d such as phenoxymethyl groups and (halogenated lower alkoxy)(lower alkyl) groups such as 2,2,2-trichloroethoxymethyl and bis(2-chloroethoxy)methyl groups; xe2x80x9c xe2x80x9clower alkoxyxe2x80x9dcarbonylxe2x80x9clower alkyl groupsxe2x80x9dxe2x80x9d such as methoxycarbonylmethyl groups; xe2x80x9ccyanoxe2x80x9clower alkyl groupsxe2x80x9dxe2x80x9d such as cyanomethyl and 2-cyanoethyl groups; xe2x80x9cxe2x80x9clower alkylxe2x80x9dthiomethyl groupsxe2x80x9d such as methylthiomethyl and ethylthiomethyl groups; xe2x80x9cxe2x80x9carylxe2x80x9dthiomethyl groupsxe2x80x9d such as phenylthiomethyl and naphthylthiomethyl groups; xe2x80x9clower alkylxe2x80x9dsulfonylxe2x80x9clower alkyl groupsxe2x80x9d which may be substituted with halogenxe2x80x9d such as 2-methanesulfonylethyl and 2-trifluoromethanesulfonylethyl groups; xe2x80x9cxe2x80x9carylxe2x80x9dsulfonylxe2x80x9clower alkyl groupsxe2x80x9dxe2x80x9d such as 2-benzenesulfonylethyl and 2-toluenesulfonylethyl groups; the above-described xe2x80x9c1-(acyloxy)xe2x80x9clower alkyl groupsxe2x80x9dxe2x80x9d; the above-described xe2x80x9cphthalidyl groupsxe2x80x9d; the above-described xe2x80x9caryl groupsxe2x80x9d; the above-described xe2x80x9clower alkyl groupsxe2x80x9d; xe2x80x9ccarboxyalkyl groupsxe2x80x9d such as carboxymethyl groups; and xe2x80x9camide forming residues of amino acidsxe2x80x9d such as phenylalanine groups.
When the compound (I) of the present invention contains an amino and/or carboxyl group, it can be converted into derivatives other than the above-described xe2x80x9cpharmacologically acceptable saltsxe2x80x9d and xe2x80x9cesters thereofxe2x80x9d. xe2x80x9cOther derivativesxe2x80x9d mean such derivatives. Examples of such derivatives include amide derivatives.
The compound (I) of the present invention contains an asymmetric carbon atom in the molecule thereof and stereoisomers whose asymmetric carbon atom has the R or S configurations are present. The stereoisomers and a mixture thereof at any ratio are also included in the present invention.
The spiropiperidine derivative of the present invention can be prepared by the below-described method.
[Method A]
In the above reaction scheme,
R1, R2, A, B, D, E, M and n have the same meanings as described above.
Yxe2x80x2 may be any group which is capable of being eliminated as a nucleophilic residue and is not specifically limited. Preferred examples of such groups include halogen atoms such as chlorine, bromine and iodine atoms; trihalomethoxy groups such as trichloromethoxy groups; lower alkanesulfonyloxy groups such as methanesulfonyloxy and ethanesulfonyloxy groups; (halogeno lower alkane)sulfonyloxy groups such as trifluoromethanesulfonyloxy and pentafluoroethanesulfonyloxy groups; and arylsulfonyloxy groups such as benzenesulfonyloxy, p-toluenesulfonyloxy and p-nitrobenzenesulfonyloxy groups, of which the halogen atoms and the lower alkanesulfonyloxy groups are still more preferred.
Step A1 is a step of preparing the compound (I) of the present invention by reacting Compound (II) with Compound (III) in a solvent in the presence of a base.
There is no particular limitation on the nature of the solvent to be employed, provided that it has no adverse effects on the reaction and can dissolve the starting materials at least to some extent. Preferred examples include aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene and dichlorobenzene; esters such as ethyl formate, ethyl acetate, propyl acetate, butyl acetate and diethyl carbonate; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and diethylene glycol dimethyl ether; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, isophorone and cyclohexanone; nitro compounds such as nitroethane and nitrobenzene; nitriles such as acetonitrile and isobutylonitrile; amides such as formamide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, N-methylpyrrolidinone and hexamethylphosphoric triamide; and sulfoxides such as dimethylsulfoxide and sulfolane, of which the amides, ethers and nitriles are more preferred and the amides are most preferred.
There is no particular limitation on the nature of the base to be employed provided that it is used in ordinary reactions. Preferred examples include combinations of a metal iodide (e.g. potassium iodide) and an inorganic base, such as an alkali metal carbonate (e.g. sodium carbonate, potassium carbonate or lithium carbonate), an alkali metal hydrogencarbonate (e.g. sodium hydrogencarbonate, potassium hydrogencarbonate or lithium hydrogencarbonate), an alkali metal hydride (e.g. lithium hydride, sodium hydride or potassium hydride), an alkali metal hydroxide (e.g. sodium hydroxide, potassium hydroxide, barium hydroxide or lithium hydroxide) or an alkali metal fluoride (e.g. sodium fluoride or potassium fluoride); or an organic base such as N-methylmorpholine, triethylamine, tripropylamine, tributylamine, diisopropylethylamine, dicyclohexylamine, N-methylpiperidine, pyridine, 4-pyrrolidinopyridine, picoline, 4-(N,N-dimethylamino)pyridine, 2,6-di(t-butyl)-4-methylpyridine, quinoline, N,N-dimethylaniline, N,N-diethylaniline, 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,4-diazabicyclo[2.2.2]octane (DABCO) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), of which the combination of a metal iodide and an inorganic base is still more preferred and the combination of a metal iodide and an alkali metal hydrogencarbonate is most preferred.
The range of reaction temperature is from 0 to 150xc2x0 C., from 20 to 120xc2x0 C.
Although the reaction time depends mainly on the reaction temperature and the nature of the raw materials, reaction reagents and solvent to be employed, the range is usually from 30 minutes to 48 hours, from 1 to 12 hours.
A compound of the formula (I) wherein a carbon atom, which is a ring-atom of group G and which is not adjacent to the piperidine ring, has a hydroxyl group can be prepared by reduction of the corresponding ketone derivative, which is prepared in accordance with the above-described Method A.
There is no particular limitation on the nature of the solvent to be employed provided that it has no adverse effects on the reaction and can dissolve the starting materials at least to some extent. Preferred examples include alcohols such as methanol and ethanol; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene and dichlorobenzene; and ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and diethylene glycol dimethyl ether, of which the alcohols are preferred and the ethanol is most preferred.
There is no particular limitation on the reducing agent to be employed provided that it is ordinarily used as a reducing agent. Preferred examples include hydride reagents such as alkali metal borohydrides (e.g. sodium borohydride or lithium borohydride), aluminum hydride compounds (e.g. lithium aluminum hydride or lithium triethoxyaluminum hydride), sodium tellurium hydride, and organic aluminum hydride reducing agents [e.g. diisobutylaluminum hydride or sodium di(methoxyethoxy)aluminum dihydride], of which the alkali metal borohydrides and organic aluminum hydride reducing agents are more preferred and the alkali metal borohydrides are most preferred.
The range of reaction temperature is from xe2x88x9278 to 50xc2x0 C., xe2x88x9220 to 20xc2x0 C.
The reaction time depends mainly on the reaction temperature, natures of the raw materials, reaction reagents and solvent to be employed. The range is usually from 5 minutes to 24 hours, 10 minutes to 2 hours.
After the completion of the respective reactions, the compounds produced by the respective reactions may be collected from the reaction mixture by a conventional process.
For example, the reaction mixture is appropriately neutralized and, after insoluble matter, if any, has been removed by filtration, a water immiscible organic solvent (e.g. ethyl acetate) is added. After washing with water and the like, the organic layer containing the desired compound is separated and dried over anhydrous magnesium sulfate and the like. Then, the solvent is distilled off to give the objective compound.
The resultant desired compound can, if desired, be isolated and purified by using conventional procedures such as recrystallization and reprecipitation, or by procedures which are conventionally used for isolation and purification of organic compounds, for example, an adsorption column chromatography process using a carrier such as silica gel, alumina or magnesium-silica gel, Florisil; a process using a synthetic adsorbent, for example, partition column chromatography using Sephadex LH-20 (manufactured by Pharmacia Co.), Amberlite XAD-11 (manufactured by Rohm and Haas Co.), Diaion HP-20 (manufactured by Mitsubishi Kasei Co., Ltd.); a process using ion-exchange chromatography; or a normal/reversed phase liquid chromatography process ( high performance liquid chromatography) using silica gel or alkylated silica gel; or in combination using a suitable eluent.
Incidentally, the raw materials are commercially available or can be prepared easily by a known method. For example, the compound of the formula (II) can be prepared by the method described in EP-776893 and the like, while the compound of the formula (III) can be prepared using methods well known in the art. See for example U.S. Pat. No. 5,578,593 and the like.
The novel spiropiperidine derivatives of the present invention exhibit excellent antagonism against tachykinin, excellent antagonistic activity against NK1, NK2 and NK3 receptors, excellent oral absorption and less toxicity so that they are useful as a medicament. Examples of the diseases for which the medicament is useful as a preventive or remedy include diseases of the central nervous system such as anxiety, depression, psychosis and schizophrenia; sleep apnea syndrome; neurodegenerative diseases such as dementia of AIDS, Alzheimer""s senile dementia, Alzheimer""s disease, Down""s syndrome, demyelinating disease, amyotrophic lateral sclerosis, neuropathy, peripheral neuropathy and neuralgia; respiratory diseases such as chronic obstructive lung diseases, bronchitis, pneumonia, bronchoconstriction, asthma and coughs; inflammatory diseases such as inflammatory bowel diseases (IBD), psoriasis, fibrositis, arthrosteitis, osteoarthritis and rheumatoid arthritis; allergic diseases such as rhinitis and eczema; hypersensitivity diseases such as hypersensitivity to vines; ophthalmological diseases such as conjunctivitis, vernal conjunctivitis, vernal catarrh, destruction of the blood-aqueous humor barrier caused by various inflammatory eye diseases, elevated in intraocular pressure and miosis; skin diseases such as contact dermatitis, atopic dermatitis, urticaria and other eczematoid dermatitis; addiction such as alcohol dependency; somatic diseases caused by stress; sympathetic reflex dystrophy such as hand and shoulder syndrome; dysthymia; undesirable immune reactions including rejection of grafts, disease relating to immunopotentiation including systemic lupus erythematosus or immunosuppression; digestive diseases including diseases caused by abnormalities in nerves regulating the organs, colitis, ulcerative colitis and Crohn""s disease; emesis including emesis induced by adverse effects of X-ray irradiation and chemotherapy, poisons, toxins, pregnancy, vestibular disorders, postoperative illness, gastrointestinal occlusion, reduced gastrointestinal movement, visceral pain, migraines, increased intracranial pressure, reduced intracranial pressure or administration of various drugs; urinary bladder functional disease such as cystitis and urinary incontinence; eosinophilia caused by collagen diseases, scieriasis or Fasciola hepatica infection; diseases caused by the abnormal blood flow due to vasodilation or vasoconstriction such as angina pectoris, migraines and Reynauds""s disease; and pain of pain nociceptive reception such as migraines, headaches and toothache.
The compound (I) of the present invention can be administered orally, for example, in the form of tablets, capsules granules, powders or syrups; administered parenterally, for example, in the form of injection preparations or suppositories; intravenously; in inhalation sprays; skin patches; etc. These preparations may be produced using pharmaceutically acceptable carriers, such as excipients [e.g. sugar derivatives, such as lactose, sucrose, glucose, mannitol, or sorbitol; starch derivatives, such as corn starch, potato starch, xcex1-starch, dextrin or carboxymethyl starch; cellulose derivatives, such as crystalline cellulose, low-substituted hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethyl-cellulose, carboxymethylcellulose calcium or internally cross-linked carboxy-methylcellulose sodium; gum arabic; dextran; organic excipients, such as pullulan; silicate derivatives, such as light anhydrous silicic acid, synthetic aluminum silicate or magnesium aluminate metasilicate; phosphates, such as calcium phosphate; carbonates, such as calcium carbonate; inorganic excipients, such as sulfates (e.g. calcium sulfate)]; lubricants [e.g. metal stearates, such as stearic acid, calcium stearate, and magnesium stearate; talc; colloidal silica; waxes, such as bee gum, and spermaceti; boric acid; adipic acid; sulfates, such as sodium sulfate; glycol; fumaric acid; sodium benzoate; DL leucine; fatty acid sodium salt; laurylsulfates, such as sodium laurylsulfate, and magnesium laurylsulfate; silicic acids, such as anhydrous silicic acid, and silicate hydrate; and the above starch derivatives]; binders [e.g. polyvinyl pyrrolidone, macrogol and the same compounds as those of the above excipients]; disintegrators [e.g. the same compounds as those of the above excipients and chemically modified starchcelluloses, such as croscarmellose sodium, carboxymethylstarch sodium and cross-linked polyvinylpyrrolidone]; stabilizers [e.g. paraoxybenzoates, such as methylparaben, and propylparaben; alcohols, such as chlorobutanol, benzyl alcohol, and phenylethyl alcohol; benzalkonium chloride; phenols, such as phenol, and cresol; thimerosal; dehydroacetic acid; and sorbic acid]; corrigents [e.g. normally used sweetening agents, sour agents, and perfumes]; and diluents according to a per se known process.
The dose varies depending on the severity of the diseases, the age of the patient (human or mammal), the administration route and the like. For example, in the case of oral administration, it is advantageous that the compound of the present invention is administered one to several times per day with a dose of from 0.01 mg/kg body weight (preferably 0.1 mg/kg body weight) lower limit to 100 mg/kg body weight (preferably 50 mg/kg body weight) upper limit according to the severity of the disease. In the case of intravenous administration, it is advantageous that the compound of the present invention is administered one to several times per day with a dose of 0.01 mg/kg body weight (preferably 0.05 mg/kg body weight) lower limit to 100 mg/kg body weight (preferably 50 mg/kg body weight) upper limit according to the severity of the disease.
The present invention provides pharmaceutical compositions comprising (i) an effective amount of the compound (I) and/or a pharmaceutically acceptable salt or ester or other derivative thereof and (ii) a pharmaceutical carrier. The present invention also provides methods to prevent or treat the diseases and conditions identified in this specification by administering an effective amount of the compound (I) or a pharmaceutically acceptable salt or ester or other derivative thereof.